Managing available resources is a key necessity of each organism to cope with the environment. The nematode C. elegans responds to nutritional deprivation or harsh environmental conditions with a ...multitude of developmental adaptations, among them a starvation-induced quiescence at early larval development (L1). daf-18, the C. elegans homolog of the human tumor suppressor gene PTEN, is essential for the maintenance of survival and germline stem cell arrest during the L1 diapause. We show here that daf-18 mutants, independently to their failure to maintain G2 arrest of the primordial germ cells, develop a gonad phenotype after refeeding. This highly penetrant gonadal phenotype is further enhanced by a mutation in shc-1, encoding a protein homologous to the human adaptor ShcA. Features of this phenotype are a tumor-like phenotype encompassing hyper-proliferation of germ cell nuclei and disruption/invasion of the basement membrane surrounding the gonad. The penetrance of this phenotype is reduced by decreasing starvation temperature. In addition, it is also ameliorated in a dose-dependent way by exposure to the antibiotic doxycyclin either during starvation or during subsequent refeeding. Since, in eukaryotic cells, doxycyclin specifically blocks mitochondrial translation, our results suggest that daf-18 and shc-1;daf-18 mutants fail to adapt mitochondrial activity to reduced nutritional availability during early larval developing.
•daf-18 and shc-1;daf-18 mutants develop a disrupted gonad after L1 starvation•hyper-proliferation and basement membrane disruption characterize this phenotype•daf-2(lf) restores proper gonad development in a DAF-16 independent manner•doxycyclin and starvation temperature decrease suffice to reduce phenotypic penetrance
Inositol 1,4,5trisphosphate (IP(3)) and diacylglycerol (DAG) are important intracellular signalling molecules in various tissues. They are generated by the phospholipase C family of enzymes, of which ...phospholipase C delta (PLCD) forms one class. Studies with functional inactivation of Plcd isozyme encoding genes in mice have revealed that loss of both Plcd1 and Plcd3 causes early embryonic death. Inactivation of Plcd1 alone causes loss of hair (alopecia), whereas inactivation of Plcd3 alone has no apparent phenotypic effect. To investigate a possible synergy of Plcd1 and Plcd3 in postnatal mice, novel mutations of these genes compatible with life after birth need to be found.
We characterise a novel mouse mutant with a spontaneously arisen mutation in Plcd3 (Plcd3(mNab)) that resulted from the insertion of an intracisternal A particle (IAP) into intron 2 of the Plcd3 gene. This mutation leads to the predominant expression of a truncated PLCD3 protein lacking the N-terminal PH domain. C3H mice that carry one or two mutant Plcd3(mNab) alleles are phenotypically normal. However, the presence of one Plcd3(mNab) allele exacerbates the alopecia caused by the loss of functional Plcd1 in Del(9)olt1Pas mutant mice with respect to the number of hair follicles affected and the body region involved. Mice double homozygous for both the Del(9)olt1Pas and the Plcd3(mNab) mutations survive for several weeks and exhibit total alopecia associated with fragile hair shafts showing altered expression of some structural genes and shortened phases of proliferation in hair follicle matrix cells.
The Plcd3(mNab) mutation is a novel hypomorphic mutation of Plcd3. Our investigations suggest that Plcd1 and Plcd3 have synergistic effects on the murine hair follicle in specific regions of the body surface.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Disturbance of cellular functions results in the activation of stress-signaling pathways that aim at restoring homeostasis. We performed a genome-wide screen to identify components of the signal ...transduction of the mitochondrial unfolded protein response (UPRmt) to a nuclear chaperone promoter. We used the ROS generating complex I inhibitor paraquat to induce the UPRmt, and we employed RNAi exposure post-embryonically to allow testing genes whose knockdown results in embryonic lethality. We identified 54 novel regulators of the ROS-induced UPRmt. Activation of the UPRmt, but not of other stress-signaling pathways, failed when homeostasis of basic cellular mechanisms such as translation and protein transport were impaired. These mechanisms are monitored by a recently discovered surveillance system that interprets interruption of these processes as pathogen attack and depends on signaling through the JNK-like MAP-kinase KGB-1. Mutation of kgb-1 abrogated the inhibition of ROS-induced UPRmt, suggesting that surveillance-activated defenses specifically inhibit the UPRmt but do not compromise activation of the heat shock response, the UPR of the endoplasmic reticulum, or the SKN-1/Nrf2 mediated response to cytosolic stress. In addition, we identified PIFK-1, the orthologue of the Drosophila PI 4-kinase four wheel drive (FWD), and found that it is the only known factor so far that is essential for the unfolded protein responses of both mitochondria and endoplasmic reticulum. This suggests that both UPRs may share a common membrane associated mechanism.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The agonist-induced dynamic regulation of the β2-adrenergic receptor (β2-AR) on living cells was examined by means of fluorescence correlation spectroscopy (FCS) using a fluorescence-labeled ...arterenol derivative (Alexa-NA) in hippocampal neurons and in alveolar epithelial type II cell line A549. Alexa-NA specifically bound to the β2-AR of neurons with a K D value of 1.29 ± 0.31 nM and of A549 cells with a K D of 5.98 ± 1.62 nM. The receptor density equaled 4.5 ± 0.9 μm-2 in neurons (ρN) and 19.9 ± 2.0 μm-2 in A549 cells (ρA549). Kinetic experiments revealed comparable on-rate constants in both cell types (k on = 0.49 ± 0.03 s-1 nM-1 in neurons and k on = 0.12 ± 0.02 s-1 nM-1 in A549 cells). In addition to the free ligand diffusing with a D free of (2.11 ± 0.04) × 10-6 cm2/s, in both cell types receptor−ligand complexes with two distinct diffusion coefficients, D bound1 (fast lateral mobility) and D bound2 (hindered mobility), were observed D bound1 = (5.23 ± 0.64) × 10-8 cm2/s and D bound2 = (6.05 ± 0.23) × 10-10 cm2/s for neurons, and D bound1 = (2.88 ± 1.72) × 10-8 cm2/s and D bound2 = (1.01 ± 0.46) × 10-9 cm2/s for A549 cells. Fast lateral mobility of the receptor−ligand complex was detected immediately after addition of the ligand, whereas hindered mobility (D bound2) was observed after a delay of 5 min in neurons (up to 38% of total binding) and of 15−20 min in A549 cells (up to 40% of total binding). Thus, the receptor−ligand complexes with low mobility were formed during receptor regulation. Consistently, stimulation of receptor internalization using the adenylate cyclase activator forskolin shifted the ratio of receptor−ligand complexes toward D bound2. Intracellular FCS measurements and immunocytochemical studies confirmed the appearance of endocytosed receptor−ligand complexes in the cytoplasm subjacent to the plasma membrane after stimulation with the agonist terbutaline (1 μM). This regulatory receptor internalization was blocked after preincubation with propranolol and with a cholesterol-complexing saponin α-hederin.
Within a two-country model with involuntary unemployment, this paper investigates corporate income taxation under separate accounting versus formula apportionment. In contrast to separate accounting, ...under formula apportionment the corporate tax policy causes a fiscal externality that results from unemployment. This externality is the highest when the apportionment formula contains the payroll factor only. It is minimized for the pure sales (property) formula, if the substitution elasticity is low (high). The unemployment externality tends to compensate other externalities such that tax rates become inefficiently low. The deviation from the efficient tax policy is minimized when the apportionment formula contains the sales factor only.
Mapping class group averages appear in the study of 3D gravity partition
functions. In this paper, we work with 3D topological field theories to
establish a bulk-boundary correspondence between such ...averages and correlators
of 2D rational CFTs whose chiral mapping class group representations are
irreducible and satisfy a finiteness property. We show that Ising-type modular
fusion categories satisfy these properties on surfaces with or without field
insertions, extending results in Jian et al., JHEP 10 (2020) 129, and we
comment on the absence of invertible global symmetries in the examples we
consider.
Pre- and post-remediation data sets are used herein to assess the effectiveness of remedial measures implemented in the headwaters of the Mineral Creek watershed, where contamination from hard rock ...mining has led to elevated metal concentrations and acidic pH. Collection of pre- and post-remediation data sets generally followed the synoptic mass balance approach, in which numerous stream and inflow locations are sampled for the constituents of interest and estimates of streamflow are determined by tracer dilution. The comparison of pre- and post-remediation data sets is confounded by hydrologic effects and the effects of temporal variation. Hydrologic effects arise due to the relatively wet conditions that preceded the collection of pre-remediation data, and the relatively dry conditions associated with the post-remediation data set. This difference leads to a dilution effect in the upper part of the study reach, where pre-remediation concentrations were diluted by rainfall, and a source area effect in the lower part of the study reach, where a smaller portion of the watershed may have been contributing constituent mass during the drier post-remediation period. A second confounding factor, temporal variability, violates the steady-state assumption that underlies the synoptic mass balance approach, leading to false identification of constituent sources and sinks. Despite these complications, remedial actions completed in the Mineral Creek headwaters appear to have led to improvements in stream water quality, as post-remediation profiles of instream load are consistently lower than the pre-remediation profiles over the entire study reach for six of the eight constituents considered (aluminium, arsenic, cadmium, copper, iron, and zinc). Concentrations of aluminium, cadmium, copper, lead, and zinc remain above chronic aquatic-life standards, however, and additional remedial actions may be needed. Future implementations of the synoptic mass balance approach should be preceded by an assessment of temporal variability, and modifications to the synoptic sampling protocol should be made if necessary. Published in 2009 by John Wiley & Sons, Ltd.
Caffeine is widely used to manage apnea of prematurity, and reduces the incidence of bronchopulmonary dysplasia (BPD). Deregulated transforming growth factor (TGF)- signaling underlies arrested ...postnatal lung maturation in BPD. It is unclear whether caffeine impacts TGF- signaling or postnatal lung development in affected lungs.
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